Phosphonate inhibitors of metallo-β-lactamases NDM-1 and VIM-2

• The upswing of antibiotic resistance is an escalating threat to human health. Resistance mediated by bacterial metallo-β-lactamases is of particular concern as these enzymes degrade β-lactams, our most frequently prescribed class of antibiotics, and they are increasingly disseminated worldwide. Inhibition of metallo-β-lactamases could allow the continued use of existing β-lactam antibiotics, such as pencillins and cephalosporins, whose applicability is becoming ever more limited. However, so far there are no clinically applicable inhibitors. The design, synthesis, and NDM-1, VIM-2, and GIM-1 inhibitory activities of a series of novel phosphonate-based inhibitor candidates is presented herein along with the solution NMR spectroscopic and computational identification of their NDM-1 and VIM-2 binding sites and binding modes. VIM-2 showed a higher conformational flexibility than NDM-1, complexed a larger number of phosphonate-based inhibitor candidates in more varying binding modes. This may indicate that it has a larger substrate promiscuity. Phosphonate-type transition-state mimicking inhibitors are demonstrated to be potential candidates for development into therapeutics to combating metallo-β-lactamase resistant bacteria

Subject headings

NATURVETENSKAP  -- Kemi -- Organisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Organic Chemistry (hsv//eng)

Publication and Content Type

vet (subject category)

ovr (subject category)